The extent of lymph node (LN) metastasis is a major determinant for the staging and the prognosis of most human malignancies and often guides therapeutic decisions.
For instance, for breast cancer, in current clinical practice, axillary lymph node involvement, age of the patient, tumour size, pathologic grade and hormone receptor status are considered as the main prognostic and/or predictive factors (Dikicioglu E. et al. 2005, Int. J. Clin. Pract. 59:1039-1044). Involvement of lymph nodes and the number of lymph nodes harbouring metastases have an inverse relationship with the disease prognosis, meaning that patients with lymph nodes free of metastases have a better outcome (Weigelt B. et al. 2004 Br. J. Cancer 90:1531-1537).
Till now, surgery is the only accurate method to identify axillary lymph node metastases. Until recently, the standard treatment for patients with operable breast cancer included the complete axillary lymph node dissection. More than half of these patients were found to have metastases-free lymph nodes and thus had been subjected to unnecessary morbidity (Harris J. R. et al. 2000 Second edition. Lippincott Williams and Wilkins, Philadelphia, p 413). The performance of selective sentinel lymph node dissection can overcome the sequelae of axillary lymph node dissection (Rietman J. S 2004 Ann. Surg. Oncol. 11:1018-1024), but is only indicated in a selected group of patients (Kuehn T. et al. 2005 Cancer 103:451-461). A less invasive method for the assessment of lymph node status is the sentinel lymph node biopsy (SLNB). Thereby, the lymphatic route of tumour cells to the lymph node(s) that primarily drains the tumour and most likely harbours metastatic disease are mapped (Giuliano A. E. et al. Ann Surg 1994, 220, 391-401).
Because lymph node involvement remains a critical benchmark in cancers such as breast cancer and is often the earliest sign of tumour progression, insights into the underlying molecular mechanisms are essential. Lymph node metastasis is a complex series of events involving the generation of new blood vessels, growth, invasion with breakdown of the host matrix, transport to other sites with adhesion and subsequent invasion (Shinozaki M. 2005 Clin. Cancer Res. 11:2156-2162). If the lymph node status can be predicted from primary cancer tissue, axillary surgery can be avoided in lymph node negative patients and for patients with isolated lymphatic drainage to non-axillary lymph nodes it will be the only way for accurate staging (and thus treatment).
The prior art also describes some methods for the prediction of the involvement of the lymph nodes without lymph node dissection or biopsy, such as the use of clinicopathologic characteristics (Nothingham Prognostic Index (NPI), includes the breast tumour diameter) the detection of altered glycosilation in the primary tumour (Brooks, S. A. et al. Lancet 1991, 338 (8759), 71-74) or of mRNA markers. However, these methods do not yield results with enough clinical significance and have other problems limiting their use in clinic.
Therefore, there is a huge need for the early, correct and easy diagnosis of lymph node involvement when tumours are identified.